Soluble estradiol capsule for vaginal insertion

ABSTRACT

According to various embodiments of this disclosure, pharmaceutical formulations comprising solubilized estradiol are provided. In various embodiments, such formulations are encapsulated in soft capsules which may be vaginally inserted for the treatment of vulvovaginal atrophy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to the following U.S. PatentApplications: U.S. Provisional Application Ser. No. 61/661,302, entitled“ESTRADIOL FORMULATIONS,” which was filed on Jun. 18, 2012; U.S.Provisional Application Ser. No. 61/662,265, entitled “PROGESTERONEFORMULATIONS,” which was filed on Jun. 20, 2012; U.S. patent applicationSer. No. 13/684,002, entitled “NATURAL COMBINATION HORMONE REPLACEMENTFORMULATIONS AND THERAPIES,” which was filed Nov. 21, 2012; U.S.Provisional Application Ser. No. 61/745,313, entitled “SOLUBLE ESTRADIOLCAPSULE FOR VAGINAL INSERTION,” which was filed on Dec. 21, 2012; U.S.Patent Application Serial No. PCT/US2013/023309, entitled “TRANSDERMALHORMONE REPLACEMENT THERAPIES,” which was filed Jan. 25, 2013; and U.S.patent application Ser. No. 13/843,428, entitled “NATURAL COMBINATIONHORMONE REPLACEMENT FORMULATIONS AND THERAPIES,” which was filed Mar.15, 2013. All aforementioned applications are hereby incorporated byreference herein in their entirety.

BACKGROUND Field

Postmenopausal women frequently suffer from certain vaginally localizedstates including, for example, atrophic vaginitis or vulvar and vaginalatrophy (hereinafter “vulvovaginal atrophy” or “VVA”) with symptomsincluding, for example, dryness, itching, soreness, irritation, bleedingand dyspareunia; with urinary frequency, urgency, urinary discomfort andincontinence also occurring (singularly and collectively,“estrogen-deficient urinary state(s)”). For the sake of clarity, theterms “atrophic vaginitis” and vulvovaginal atrophy are used hereininterchangeably. The molecular morphology of VVA is well known in themedical field.

Each of these VVA-related states, inter alia, are symptoms associatedwith decreased estrogenization of the vulvovaginal tissue, and can evenoccur in women treated with oral administration of an estrogen-basedpharmaceutical drug product. Although VVA is most common with menopausalwomen, it can occur at any time in a woman's life cycle.

VVA-related states are generally treated with local administration of anestrogen-based natural or synthetic hormone in the form of a topicallyapplied gel or cream, or through vaginal insertion of a compressedtablet. These forms of administration can provide low levels ofcirculating estrogen but are not intended to contribute to the treatmentof other states related to estrogen deficiencies typically treated viaadministration of a systemically absorbed estrogen product.

For example, such systemically absorbed products include orallyadministered formulations as well as creams, gels, sprays, andtransdermally delivered products. However, vaginal gels and creams mayrub, wear or wash off before the estrogen is fully absorbed into thelocal tissue. In addition, various commercially availableestrogen-containing creams contain an alcohol such as benzyl alcoholand/or stearyl alcohol. The use of such products may result in itchingor burning when applied. The above referenced vaginal creams and gelsrequire insertion via a reusable vaginal applicator/plunger for whichpatients complain of difficulty to accurately dose, discomfort or painupon insertion, and increased trauma to the genital mucosa all inrelation to the vaginal applicator. Furthermore, the reusableapplicator/plunger is also difficult to clean resulting in hygienicconcerns as well as increased rates of infection all decreasing theongoing compliance of the therapy.

Similarly, vaginal suppositories in the form of inserted tablets may notfully dissolve, reducing the effective dose of absorbed estrogen; maycause unwanted and unnecessary vaginal discharge; may cause an increaseof vulvovaginal pruritus and/or back pain; and the insertion, itself,using the applicator provided with the reference-listed tableted drug,Vagifem® (Novo Nordisk; Princeton, N.J.), may cause a rupture of thevaginal fornix.

There has been at least one attempt at providing a soluble or suspendedestrogen capsule for vaginal insertion as described in U.S. Pat. No.6,060,077 (the '077 patent). The '077 patent provides for a non-systemictreatment for vaginal dryness in menopausal women using an immediate orslow-release formulation comprising a natural estrogen compound insolution or suspension in a lipophilic agent, a hydrophilic gel-formingbioadhesive agent, a gelling agent for the lipophilic agent, and ahydrodispersible agent in a hard or soft capsule. It is specificallystated that these formulations are designed to avoid systemic passage ofestradiol following administration. Once in contact with vaginalsecretions, these formulations require the presence of the hydrophilicgel-forming bioadhesive agent to react with the hydrodispersible agentto form an estrogen-containing emulsion to facilitate absorption. Apractical issue arises when attempting to use this medicament whenvaginal secretions are required to activate the formulation while thetreatment is designed to treat vaginal dryness.

Accordingly, an estrogen-based vaginal suppository that provides an easeof administration/insertion, improved safety of insertion, lacking orminimizing vaginal discharge following administration, and that does notrequire vaginal secretions to activate the formulation could provide amore effective dosage form with improved efficacy, safety and patientcompliance.

SUMMARY

According to various embodiments of this disclosure, encapsulatedpharmaceutical formulations comprising solubilized estradiol areprovided. Such formulations are encapsulated in soft capsules which arevaginally inserted for the treatment of vulvovaginal atrophy.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter of the present invention is particularly pointed outand distinctly claimed below. A more complete understanding of thepresent invention, however, may best be obtained by referring to thedetailed description and claims when considered in connection with thefigures, wherein like numerals denote like elements and wherein:

FIG. 1 is a flow diagram illustrating a process in accordance withvarious embodiments of the invention; and

FIG. 2 illustrates a suppository in accordance with various embodimentsof the invention.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS Definitions

The term “active pharmaceutical ingredient” as used herein, means theactive compound(s) used in formulating a drug product.

The term “AUC,” as used herein, refers to the area under the curve thatrepresents changes in blood concentration of an active pharmaceuticalingredient (e.g., estradiol, which is also referred to in the literatureas 17β-estradiol, oestradiol, or E2) over time.

The term “bioavailability”, as used herein means the concentration of anactive ingredient (e.g., estradiol) in the blood (serum or plasma). Therelative bioavailability may be measured as the concentration in theblood (serum or plasma) versus time. Pharmacokinetic (PK) indicatorsthat may be used to measure and assess bioavailability are determined bysuitable metrics including AUC, Cmax, and, optionally, Tmax.

The term “bioequivalent” means that a test drug product provides similarbioavailability compared to a reference drug product pursuant to thecriteria set forth for bioequivalence by the United States Food and DrugAdministration, as amended. In general, the bioavailability of an activepharmaceutical ingredient in a bioequivalent drug product is 80 to 125%of the bioavailability of the active pharmaceutical ingredient of thereference drug product concerning AUC and Cmax.

The term “bio-identical hormones”, as used herein, means thosesynthetically-derived compounds which are identical in chemicalstructure to the hormones naturally produced in vivo. These natural orbio-identical hormones are synthesized from various ingredients to matchthe chemical structure and effect of estradiol or estrone, or estriol(the 3 primary estrogens).

The term, “Cmax” as used herein, refers to the maximum value of bloodconcentration shown on the curve that represents changes in bloodconcentrations of an active pharmaceutical ingredient (e.g., estradiol)over time.

The term “co-administered” as used herein, means that two drug productsare administered simultaneously or sequentially on the same or differentdays.

The term “drug product” as used herein means at least one activepharmaceutical ingredient in combination with at least one excipient andprovided in unit dosage form.

The term “excipients,” as used herein, refer to non-activepharmaceutical ingredients such as carriers, solubilizing agents, oils,lubricants and others used in formulating pharmaceutical products. Theyare generally safe for administering to animals, including humans,according to established governmental standards, including thosepromulgated by the United States Food and Drug Administration.

The term “natural,” as used herein with reference to hormones discussedherein, means bio-identical hormones synthesized to match the chemicalstructure and effect of those that occur naturally in the human body(endogenous). An exemplary natural estrogen is estradiol (also describedas 17β-estradiol and E2).

The term “medium chain,” as used herein means any medium chaincarbon-containing substance, including C4-C18, and including C6-C12substances, fatty acid esters of glycerol, fatty acids, and mono-, di-,and triglycerides of such substances. For further illustration, C6-C14,C6-C12 fatty acids, and C8-C10 fatty acids are all medium chain fattyacids and may be used in instances in which this specification calls foruse of medium chain fatty acids, e.g., medium chain fatty acid esters ofglycerol or other glycols.

The term “reference listed drug product” as used herein means Vagifem®.

The term “solubilizer,” as used herein, means any substance or mixtureof substances that may be used to enhance the solubility of estradiol,including, for example and without limitation, appropriatepharmaceutically acceptable excipients, such as solvents, co-solvents,surfactants, emulsifiers, oils and carriers.

The term “treatment”, as used herein, or a derivative thereof,contemplates partial or complete inhibition of the stated disease stateor condition when a formulation as described herein is administeredprophylactically or following the onset of the disease state for whichsuch formulation is administered. For the purposes of the presentdisclosure, “prophylaxis” refers to administration of the activeingredient(s) to an animal, typically a human, to protect the animalfrom any of the disorders set forth herein, as well as others.

The term, “Tmax” as used herein, refers to the time that it takes for anactive pharmaceutical ingredient (e.g., estradiol) and/or estrone bloodconcentrations to reach the maximum value.

Description

Provided herein are pharmaceutical formulations comprising solubilizedestradiol (in various embodiments, at least 90% in solution); providingsaid formulations do not embrace within the fill one or more of thefollowing components: a hydrophilic gel-forming bioadhesive (e.g.,mucoadhesive) agent; a lipophilic agent; a gelling agent for thelipophilic agent, and/or a hydrodispersible agent. The hydrophilicgel-forming bioadhesive agent may provide or exclude one or more of a:carboxyvinylic acid; hydroxypropylcellulose; carboxymethylcellulose;gelatin; xanthane gum; guar gum; aluminum silicate; or mixtures thereof.The lipophilic agent may provide or exclude one or more of a: liquidtriglyceride; solid triglyceride (with a melting point of about 35° C.);carnauba wax; cocoa butter; or mixtures thereof. The gelling agent mayprovide or exclude one or more of a hydrophobic colloidal silica. Thehydrodispersible agent may provide or exclude one or more of a:polyoxyethylene glycol; polyoxyethylene glycol 7-glyceryl-cocoate andmixtures thereof.

Generally, the pharmaceutical formulations described herein are preparedand administered as filled capsules, typically soft capsules of one ormore materials well known in the art including, for example and withoutlimitation, soft gelatin capsules. However, in various embodiments,pharmaceutical formulations described herein are prepared as a gel,cream, ointment, transdermal delivery system or like preparation.

Other aspects of the present disclosure include the use of formulationsas described herein for the treatment of vulvovaginal atrophy includingthe treatment of at least one VVA symptom including, for example andwithout limitation, dryness, itching, soreness, irritation, bleeding anddyspareunia.

Another aspect of the present disclosure provides uses of theformulations described herein for the treatment of estrogen-deficienturinary states.

Another aspect of the present disclosure provides alcohol-free orsubstantially alcohol-free formulations, and uses thereof. Among others,the formulations offer improved comfort during use, thus tending toenhance patient compliance.

The methods of treatment described herein are generally administered toa human female.

A further aspect of the present invention provides formulations of thepresent invention wherein circulating blood level concentrationsfollowing administration of a formulation of the present invention arebioequivalent to circulating blood level concentrations followingadministration of the reference listed drug product, as determinedthrough the completion of a bioequivalence clinical study.

The formulations of the present disclosure may also be vaginallyadministered with or without the co-administration of an orallyadministered estrogen-based (or progestin-based or progestin- andestrogen-based) pharmaceutical drug product, or patch, cream, gel,spray, transdermal delivery system or other parenterally-administeredestrogen-based pharmaceutical drug product, each of which can includenatural, bio-similar, or other synthetic or derived estrogens and/or anadministered progestin. As used herein, the term “progestin” means anynatural or man-made substance that has pharmacological propertiessimilar to progesterone.

Modulation of circulating estrogen levels provided via theadministration of a formulation of the present disclosure, if any, arenot intended to be additive to any co-administered estrogen product andits associated circulating blood levels.

The timing of administration of a formulation of the present disclosuremay be conducted by any safe means as prescribed by an attendingphysician. Typically, a patient will insert one capsule intra-vaginallyeach day for 14 days, then one capsule twice weekly for the remainingtime prescribed by such physician. Intra-vaginal insertion may be viathe use of an applicator or without an applicator via use of thepatient's digits. Use of an applicator or otherwise requires due care asto not puncture or tear surrounding tissue.

Estradiol dosage strengths can vary. For formulations of the presentdisclosure, estradiol (or estradiol equivalent to the extent suchestradiol is in a hydrated or other form requiring compensationtherefore) dosage strength of is at least about 1 microgram (mcg), atleast about 2.5 mcg; at least about 5 mcg; at least about 10 mcg, fromabout 1 mcg to about 10 mcg, from about 10 mcg to about 25 mcg, about 1mcg, about 2.5 mcg, about 5 mcg, about 10 mcg and about 25 mcg. Toprotect against adverse effects of estradiol, the lowest possible doseshould be used for treatment of VVA and other states set forth herein.In one embodiment, the dosage is about 10 mcg; in another the dosage isabout 25 mcg.

Also provided are soft capsules designed for ease of insertion and tohold the capsule in place until the contents therein are completelyreleased. In various embodiments, softgel capsules in accordance withvarious embodiments are sized to comfortably fit within a human vagina.Thus, the softgel capsules may comprise any dimension capable of fittinginto a human vagina. With reference to FIG. 2, softgel capsule 200 isillustrated. Softgel capsule 200 comprises fill material 202 and gelatin204. Gelatin 204 has a thickness represented by space 208. Space 208comprises a distance of 0.108 inches. The distance from one end ofsoftgel capsule 200 to another is represented by space 206. Space 206comprises a distance of 0.690 inches. The size of softgel capsule 200may also be described by the arc swept by a radius of a given length.For example, arc 210, which is defined by the exterior of gelatin 204,is an arc swept by a radius of 0.189 inches. Arc 212, which is definedby the interior of gelatin 204, is an arc swept by a radius of 0.0938inches. Arc 214, which is defined by the exterior of gelatin 204opposite arc 210, is an arc swept by a radius of 0.108 inches.

Estradiol can be formulated pursuant to the teachings below. Theseformulations can be prepared for vaginal insertion in a single unitdosage form or as otherwise specified herein.

In various embodiments, estradiol is solubilized at least once duringmanufacturing and, in various embodiments, estradiol is solubilized atone point following administration. Solubility may be expressed as amass fraction (% w/w). As used herein, the term “soluble” or“solubilized” means that the estradiol is: at least about 85% soluble,at least 90% soluble, at least 95% soluble and, frequently, is 100%soluble. % Solubility is expressed herein as a mass fraction (% w/w,also referred to as wt %).

Upon release of the fill into the vaginal canal following insertion of acapsule of the present disclosure, estradiol may be locally absorbedinto body tissues.

In various embodiments, the solubilizing agent is selected from at leastone of a solvent or co-solvent. Suitable solvents and co-solventsinclude any mono-, di- or triglyceride and glycols, and combinationsthereof.

Solubilized estradiol of the present disclosure is prepared via blendingestradiol with a pharmaceutically acceptable solubilizing agentincluding for example and without limitation, at least one medium chainfatty acid such as medium chain fatty acids consisting of at least onemono-, di-, or triglyceride, or derivatives thereof, or combinationsthereof (collectively, “glycerides”). In various embodiments,solubilized estradiol of the present disclosure may also comprise atleast one glycol or derivatives thereof or combinations thereof(collectively, “glycols”) and/or combinations of such at least oneglyceride and glycol. Glycols may be used as solubilizing agents and/orto adjust viscosity and, thus, may be considered thickening agents, asdiscussed further herein. Optionally added are other excipientsincluding, for example and without limitation, anti-oxidants, lubricantsand the like. Sufficient solubilizing agent(s) is/are used to solubilizeestradiol.

Pharmaceutically acceptable solubilizing agents include, for example andwithout limitation, the use of at least one of a caproic fatty acid; acaprylic fatty acid; a capric fatty acid; a tauric acid; a myristicacid; a linoleic acid; a succinic acid; a glycerin; mono-, di-, ortriglycerides and combinations and derivatives thereof; a polyethyleneglycol; a polyethylene glycol glyceride (GELUCIRE (polyethylene glycolglyceride) GATTEFOSSE SAS, Saint-Priest, France); which can be usedherein as a solubilizing agent or as an anionic surfactant); a propyleneglycol; a caprylic/capric triglyceride (MIGLYOL (caprylic/caprictriglyceride)); SASOL Germany GMBH, Hamburg); MIGLYOL includes MIGLYOL810 (caprylic/capric triglyceride), MIGLYOL 812 (caprylic/caprictriglyceride), MIGLYOL 816 (caprylic/capric triglyceride) and MIGLYOL829 (caprylic/capric/succinic triglyceride)); acaproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleictriglyceride; a caprylic/capric/succinic triglyceride; a propyleneglycol monocaprylate; propylene glycol monocaprate; (CAPMUL PG-8(propylene glycol monocaprylate) and CAPMUL PG-10 (propylene glycolmonocaprate); the CAPMUL brands are owned by ABITEC, Columbus Ohio); apropylene glycol mono- and dicaprylate; a propylene glycol mono- anddicaprate; medium chain mono- and di-glycerides (CAPMUL MCM (mediumchain mono- and diglycerides)); a diethylene glycol mono ester(including 2-(2-Ethoxyethoxy)ethanol: TRANSCUTOL (diethylene glycolmonoethyl ether)); a diethylene glycol monoethyl ether; glyceryl mono-and di-caprylates; propylene glycol; 1,2,3-propanetriol (glycerol,glycerin, glycerine) esters of saturated coconut and palm kernel oil andderivatives thereof; triglycerides of fractionated vegetable fattyacids, and combinations and derivatives thereof. In various embodiments,propylene glycol is used in a cream or ointment.

These solubilizers, as defined herein, and combinations thereof, can beused to form solubilized estradiol formulations of the presentdisclosure.

At least one anionic and/or non-ionic surfactant can be used inadditional embodiments of the presently disclosed formulationscontaining solubilized estradiol.

Exemplary non-ionic surfactants may include, for example and withoutlimitation, one or more of oleic acid, linoleic acid, palmitic acid, andstearic acid. In further embodiments, the non-ionic surfactant maycomprise polyethylene sorbitol esters, including polysorbate 80, whichis commercially available under the trademark TWEEN 80 (polysorbate 80)(Sigma Aldrich, St. Louis, Mo.). Polysorbate 80 comprises approximately60%-70% oleic acid with the remainder comprising primarily linoleicacids, palmitic acids, and stearic acids. Polysorbate 80 may be used inamounts ranging from about 5 to 50%, and in certain embodiments, about30% of the formulation total mass. In various other embodiments, thenon-ionic surfactant is selected from one or more of glycerol andpolyethylene glycol esters of long chain fatty acids, for example,lauroyl macrogol-32 glycerides and/or lauroyl polyoxyl-32 glycerides,commercially available as GELUCIRE, including, for example, GELUCIRE39/01 (glycerol esters of saturated C12-C18 fatty acids), GELUCIRE 43/01(hard fat NF/JPE) and GELUCIRE 50/13 (stearoyl macrogol-32 glyceridesEP, stearoyl polyoxyl-32 glycerides NF, stearoyl polyoxylglycerides (USAFDA IIG)). These surfactants may be used at concentrations greater thanabout 0.01%, and typically in various amounts of about 0.01%-10.0%,10.1%-20%, and 20.1%-30%.

Ratios of solubilizing agent(s) to surfactant(s) can vary depending uponthe respective solubilizing agent(s) and the respective surfactant(s)and the desired physical characteristics of the resultant formulation ofsolubilized estradiol. For example and without limitation, CAPMUL MCMand a non-ionic surfactant can be used at ratios including 65:35, 70:30,75:25, 80:20, 85:15 and 90:10. Other non-limiting examples include:CAPMUL MCM and GELUCIRE 39/01 can be used in ratios including, forexample and without limitation, 6:4, 7:3, and 8:2; CAPMUL MCM andGELUCIRE 43/01 can be used in ratios including, for example and withoutlimitation, 7:3, and 8:2; CAPMUL MCM and GELUCIRE 50/13 can be used inratios including, for example and without limitation, 7:3, and 8:2, and9:1.

Another exemplary non-ionic surfactant includes PEG-6 palmitostearateand ethylene glycol palmitostearate, which is available commercially asTEFOSE 63 (“Tefose 63”; GATTEFOSSE SAS, Saint-Priest, France) which canbe used with, for example, CAPMUL MCM having ratios of MCM to TEFOSE 63of, for example, 8:2 and 9:1. Additional examples of solubilizing agentswith non-ionic surfactants include, for example, MIGLYOL 812:GELUCIRE50/13 and MIGLYOL 812:TEFOSE 63.

Anionic surfactants are well known and can include, for example andwithout limitation: ammonium lauryl sulfate, dioctyl sodiumsulfosuccinate, perfluoro-octane sulfonic acid, potassium lauryl sulfateand sodium stearate.

Non-ionic and/or anionic surfactants can be used alone or with at leastone solubilizing agent or can be used in combination with othersurfactants. Accordingly, such surfactants, or any other excipient asset forth herein, should be used to provide solubilized estradiol, uponrelease from a vaginally-inserted capsule, with consistency of thesolubilized estradiol that promotes absorption and minimizes vaginaldischarge, particularly when compared to the vaginal dischargefrequently occurring following use of a VAGIFEM tablet.

Moreover, the estradiol in the formulations disclosed herein need not befully solubilized (e.g., at least 98% in solution) at the time ofadministration/insertion but, rather, needs to be substantiallysolubilized at the time of release from the vaginally-inserted capsule.As such, the solubilizing agents taught herein, with or withoutadditional excipients other than the solubilizing agents, may be in theliquid or semi-solid form upon administration providing the estradiolcontaining solubilizing agents and other excipients permit flow to fillcapsules. To the extent the estradiol is not fully solubilized at thetime of administration/insertion, the estradiol should be substantiallysolubilized at a temperature of about 37° C. (e.g., body temperature)and, generally, at a pH of about 4.5. In another embodiment, at leastone thickening agent may be added to formulations of the presentdisclosure. The viscosity of the solubilized estradiol may depend uponthe solubilizing agent(s) used, the addition of other excipients to theformulation preparation and the desired or required final viscosityrequired to optimize absorption of the solubilized estradiol. In certainembodiments, the surfactant(s) referenced herein above may providethickening of the solubilized estradiol such that, upon release, willaid the estradiol in being absorbed by the vaginal mucosa whileminimizing vaginal discharge, particularly when compared to the vaginaldischarge frequently occurring following use of a Vagifem tablet.Examples of other such thickening agents include, for example andwithout limitation, hard fats; propylene glycol; a mixture of hard fatEP/NF/JPE, glyceryl ricinoleate, ethoxylated fatty alcohols (ceteth-20,steareth-20) EP/NF (commercially available as OVUCIRE 3460 (mixture ofhard fat EP/NF/JPE (and) glyceryl ricinoleate (and) ethoxylated fattyalcohols (ceteth-20, steareth-20) EP/NF) (Gattefosse, Saint-PriestFrance); a mixture of hard fat EP/NF/JPE, glycerol monooleate (type 40)EP/NF (commercially available as OVUCIRE WL 3264 (mixture of hard fatEP/NF/JPE (and) glycerol monooleate (type 40) EP/NF); a mixture of hardfat EP/NF/JPE, glyceryle monooleate (type 40) EP/NF (commerciallyavailable as OVUCIRE WL 2944 (mixture of hard fat EP/NF/JPE (and)glyceryle monooleate (type 40) EP/NF)); and a mixture of various hardfats (commercially available as WITESPOL (hard fats); Sasol GermanyGmbH, Hamburg). In various embodiments, the viscosity of formulations inaccordance with various embodiments may comprise from about 50 cps toabout 1000 cps at 25° C.

In other embodiments, one or more muco-adherent agents may be used toassist with mucosal absorption of the solubilized estradiol. Forexample, polycarbophil may be used as an acceptable muco-adherent agent.Other agents include, for example and without limitation, poly (ethyleneoxide) polymers having a molecular weight of from about 100,000 to about900,000, chitosans carbopols including polymers of acrylic acidcrosslinked with allyl sucrose or allyl pentaerythritol, polymers ofacrylic acid and C10-C30 alkyl acrylate crosslinked with allylpentaerythritol, carbomer homopolymer or copolymer that contains a blockcopolymer of polyethylene glycol and a long chain alkyl acid ester andthe like. Various hydrophilic polymers and hydrogels may be used. Invarious embodiments, the hydrophilic polymer will swell in response tocontact with vaginal or other bodily secretions, enhancing moisturizingand muco-adherent effects. The selection and amount of hydrophilicpolymer may be based on the selection and amount of pharmaceuticallyacceptable solubilizing agent chosen. The formulation includes ahydrophilic polymer but optionally excludes a gelling agent. Inembodiments having a hydrogel, from about 5% to about 10% of the totalmass may comprise the hydrophilic polymer. In further embodiments,hydrogels may be employed. A hydrogel may comprise chitosan, which swellin response to contact with water. In various embodiments, a creamformulation may comprise PEG-90M.

In additional embodiments, formulations of the present disclosure mayinclude one or more thermoreversible gels, typically of the hydrophilicnature including for example and without limitation, hydrophilic sucroseand other saccharide-based monomers (U.S. Pat. No. 6,018,033, which isherein incorporated by reference).

In other embodiments, a lubricant may be used. Any suitable lubricantmay be used, such as for example lecithin. Lecithin may comprise amixture of phospholipids.

In additional embodiments, an antioxidant is used. Any suitableantioxidant may be used such as, for example and without limitation,butylated hydroxytoluene.

In various embodiments, a pharmaceutical formulation comprises about 20%to about 80% solubilizing agent by weight, about 0.1% to about 5%lubricant by weight, and about 0.01% to about 0.1% antioxidant byweight.

The choice of excipient will, to a large extent, depend on factors suchas for example and without limitation, the effect of the excipient onsolubility and stability. Additional excipients used in variousembodiments may include colorants and preservatives. Colorants, forexample, may comprise about 0.1% to about 2% by weight. Preservativesmay, for example and without limitation, comprise methyl and propylparaben, for example, in a ratio of about 10:1, and at a proportion ofabout 0.005% and 0.05% by weight.

As is with all solubilizing agents, excipients and any other additivesused in the formulations described herein, each is to be non-toxic,pharmaceutically acceptable and compatible with all other ingredientsused.

Further provided herein are methods for the treatment of VVA and/orestrogen-deficient urinary states comprising administering to a female,typically a human, in need of treatment a non-toxic and pharmaceuticallyeffective dose of a formulation as further provided herein.

As referenced above, the formulations of the present disclosure aregenerally vaginally administered via capsules such as soft capsules,including soft gelatin capsules. It is desirable to prepare these softcapsules such that they disintegrate to the extent that substantiallyall of the solubilized estradiol is released upon disintegration,providing rapid absorption of the solubilized estradiol and minimal tono capsule residue.

Additional objects of the present disclosure include: providingincreased patient ease of use while potentially minimizing certain sideeffects from inappropriate insertion, minimizing incidence ofvulvovaginal mycotic infection compared to incidence of vulvovaginalmycotic infection due to usage of Vagifem and other currently availableproducts and; decreased resultant genital pruritus compared to thegenital pruritus and/or back pain that may be generated via the use ofVagifem and other currently available products. In illustrativeembodiments of the invention, oils are used as solubilizing agents tosolubilize estradiol and include medium chain fatty acid esters, (e.g.,esters of glycerol, polyethylene glycol, or propylene glycol) andmixtures thereof. In illustrative embodiments, the medium chain fattyacids are C6 to C14 or C6 to C12 fatty acids. In illustrativeembodiments, the medium chain fatty acids are saturated, orpredominantly saturated, e.g., greater than about 60% or greater thanabout 75% saturated. In illustrative embodiments, estradiol is solublein the oils at room temperature, although it may be desirable to warmcertain oils initially during manufacture to improve viscosity. Inillustrative embodiments, the oil or oil/thickening agent is liquid atbetween room temperature and about 50° C., e.g., at or below 50° C., ator below 40° C., or at or below 50° C. In illustrative embodiments,GELUCIRE 44/14 (lauroyl macrogol-32 glycerides EP lauroyl polyoxyl-32glycerides NF lauroyl polyoxylglycerides (USA FDA IIG)) is heated toabout 65° C. and CAPMUL MCM is heated to about 40° C. to facilitatemixing of the oil and non-ionic surfactant, although such heating is notnecessary to dissolve the estradiol. In illustrative embodiments, thesolubility of estradiol in the oil (or oil/surfactant) is at least about0.5 wt %, e.g., 0.8 wt % or higher, or 1.0 wt % or higher. Illustrativeexamples of mono- and diglycerides of medium chain fatty acids include,among others, CAPMUL MCM, CAPMUL MCM C10 (glyceryl monocaprate), CAPMULMCM C8 (glyceryl monocaprylate), and CAPMUL MCM C8 EP (glycerylmonocaprylate). These oils are C8 and C10 fatty acid mono- anddiglycerides. Illustrative examples of oils that are triglycerides ofmedium chain fatty acids include, among others, MIGLYOL 810 and M IGLYOL812. Illustrative examples of oils that are medium chain fatty acidesters of propylene glycol include, among others, CAPMUL PG-8, CAPMULPG-2L EP/NF (propylene glycol dilaurate), CAPMUL PG-8 NF (propyleneglycol monocaprylate), CAPMUL PG-12 EP/NF (propylene glycol monolaurate)and CAPRYOL (propylene glycol monocaprylate (type II) NF). Otherillustrative examples include MIGLYOL 840 (propylene glycoldicaprylate/dicaprate).

Illustrative examples of oils that are medium chain fatty acid esters ofpolyethylene glycol include, among others, GELUCIRE 44/14 (PEG-32glyceryl laurate EP), which is polyethylene glycol glycerides composedof mono-, di- and triglycerides and mono- and diesters of polyethyleneglycol.

These illustrative examples comprise predominantly medium chain length,saturated, fatty acids (i.e., greater than 50% of the fatty acids aremedium chain saturated fatty acids); specifically predominantly C8 toC12 saturated fatty acids.

It will be understood that commercially available fatty acid esters ofglycerol and other glycols are often prepared from natural oils andtherefore may comprise components additional to the fatty acid estersthat comprise the predominant (by weight) component(s) and thattherefore are used to characterize the product. Such other componentsmay be, e.g., other fatty acid triglycerides, mono- and diesters, freeglycerol, or free fatty acids. So, for example, when an oil/solubilizingagent is described herein as a saturated C8 fatty acid mono- or diesterof glycerol, it will be understood that the predominant component of theoil, i.e., >50 wt % (e.g., >75 wt %, >85 wt % or >90 wt %) are caprylicmonoglycerides and caprylic diglycerides. For example, the TechnicalData Sheet by ABITEC for CAPMUL MCM C8 describes CAPMUL MCM C8 as beingcomposed of mono and diglycerides of medium chain fatty acids (mainlycaprylic) and describes the alkyl content as <=1% C6, >=95% C8, <=5%C10, and <=1.5% C12 and higher

By way of further example, MIGLYOL 812 is generally described as aC8-C10 triglyceride because the fatty acid composition is at least about80% caprylic (C8) acid and capric (C10) acid. However, it can alsocomprise small amounts of other fatty acids, e.g., less than about 5% ofcaproic (C6) acid, lauric (C12) acid, and myristic (C14) acid.

Specifically, a product information sheet for MIGLYOL by SASOL providesthe composition of fatty acids as follows:

Tests 810 812 818 829 840 Caproic acid (C6:0) max. 2.0 max. 2.0 max. 2max. 2 max. 2 Caprylic acid (C8:0) 65.0-80.0 50.0-65.0 45-65 45-55 65-80Capric acid (C10:0) 20.0-35.0 30.0-45.0 30-45 30-40 20-35 Lauric acid(C12:0) max. 2   max. 2   max. 3 max. 3 max. 2 Myristic acid max. 1.0max. 1.0 max. 1 max. 1 max. 1 (C14:0) Linoleic acid — — 2-5 — — (C18:2)Succinic acid — — — 15-20 —

So, if an embodiment of this invention is described as comprising (orconsisting essentially of) a capsule shell, estradiol solubilized inC8-C10 triglycerides, and a thickening agent, it will be understood thatthe fatty acid esters component of the formulation may be, e.g., MIGLYOL812 or a similar product.

By way of further illustration, GELUCIRE 44/14 is generally described aslauroyl polyoxyl-32 glycerides, i.e., polyoxyethylene 32 lauricglycerides (which is a mixture of mono-, di-, and triesters of glyceroland mono- and diesters of PEGs) because the fatty acid composition is 30to 50% lauric acid and smaller amounts of other fatty acids, e.g., up to15% caprylic acid, up to 12% capric acid, up to 25% myristic acid, up to25% palmitic acid, and up to 35% stearic acid. The product may alsocontain small amounts of non-esterified glycols. So, if an embodiment ofthis invention is described as comprising (or consisting essentially of)a capsule shell, estradiol solubilized in triglycerides, and athickening agent that is a non-ionic surfactant comprising C8 to C18fatty acid esters of glycerol and polyethylene glycol, it will beunderstood that the thickening agent component of the formulation maybe, e.g., GELUCIRE 44/14 or a similar product.

Similarly, if an embodiment of this invention is described as comprising(or consisting essentially of) a capsule shell, estradiol solubilized intriglycerides, and a thickening agent that is a non-ionic surfactantcomprising PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32stearate, it will be understood that the thickening agent component ofthe formulation may be, e.g., TEFOSE 63 or a similar product.

Mixtures of medium chain fatty acid glycerides, e.g., C6-C12, C8-C12, orC8-C10 fatty acid mono- and diglycerides or mono-, di-, andtriglycerides are very well suited for dissolving estradiol; goodresults have been obtained with an oil that is predominantly a mixtureof C8-C10 saturated fatty acid mono- and diglycerides. Longer chainglycerides appear to be not as well suited for dissolution of estradiol.

High solubility of estradiol has been obtained in2-(2-Ethoxyethoxy)ethanol, e.g., TRANSCUTOL and in Propylene glycolmonocaprylate, e.g., Capryol™ 90 (Gattefosse).

In various embodiments, the solubilizing agent is selected from at leastone of a solvent or co-solvent. Suitable solvents and co-solventsinclude any mono-, di- or triglyceride and glycols, and combinationsthereof.

In addition, other solubilizers include, for example and withoutlimitation, glyceryl mono- and di-caprylates, propylene glycol and1,2,3-propanetriol (glycerol, glycerin, glycerine).

Illustrative Drug Product(s)

Through extensive trial-and-error testing of various fatty acid estersof glycerol and other glycols, embodiments of the invention have beeninvented that have one or more favorable characteristics for developmentas a human drug product. Such favorable characteristics include, e.g.,lack of or reduction of irritation relative to otherwise similarformulations, lack of or reduction in vaginal discharge of drug productrelative to otherwise similar formulations, lack of or reduction of drugproduct residue inside the vagina, etc. Non-irritating formulations areformulations that in most uses in most patients, when used asprescribed, does not cause pain, soreness, swelling or irritation insidethe vagina such that most patients do not go off treatment prior tocompletion of a prescribed course of therapy. Non-irritatingformulations are also formulations that are non-irritating, as describedin the preceding sentence, relative to competing products such astablets, creams, or other intravaginal estrogen delivery forms. Suchillustrative drug products are also easily self-administered by apatient in any position by inserting the encapsulated formulationdigitally approximately 2 inches into her vagina without a need for anapplicator and with minimal to no corresponding discharge.

Formulations that do not create a residue are formulations that areabsorbed and/or dispersed without resulting in particulates or otherunpleasant remains of non-absorbed or non-dispersed drug product. Again,lack of residue can be relative to competing products.

Formulations that do not discharge from the vagina are formulations thatdo not flow or drip out of the vagina. Again, lack of discharge can berelative to competing products.

Such embodiments include an encapsulated liquid pharmaceuticalformulation for intra-vaginal delivery of estradiol, said formulationcomprising estradiol that is at least about 90% solubilized in one ormore C6 to C14 fatty acid mono-, di-, or triesters of glycerol and athickening agent.

A more specific such embodiment is such formulation wherein theestradiol is solubilized (e.g., >90% solubilized) in one or more C6 toC12 fatty acid mono-, di-, or triesters of glycerol, e.g., one or moreC6 to C14 triglycerides, e.g., one or more C6 to C12 triglycerides, suchas one or more C8-C10 triglycerides.

In such general and more specific embodiments, the thickening agent canbe a non-ionic surfactant, e.g., a polyethylene glycol saturated orunsaturated fatty acid ester or diester. In certain such embodiments,the non-ionic surfactant comprises a polyethylene glycol long chain(C16-C20) fatty acid ester and further comprises an ethylene glycol longchain fatty acid ester, such as PEG-fatty acid esters or diesters ofsaturated or unsaturated C16-C18 fatty acids, e.g., oleic, lauric,palmitic, and stearic acids. In certain such embodiments, the non-ionicsurfactant comprises a polyethylene glycol long chain saturated fattyacid ester and further comprises an ethylene glycol long chain saturatedfatty acid ester, such as PEG- and ethylene glycol-fatty acid esters ofsaturated C16-C18 fatty acids, e.g., palmitic and stearic acids. Suchnon-ionic surfactant can comprise PEG-6 stearate, ethylene glycolpalmitostearate, and PEG-32 stearate, such as but not limited to TEFOSE63.

In certain such embodiments, the non-ionic surfactant employed as thethickening agent is not hydrophilic and has good emulsion properties. Anillustrative example of such surfactant is TEFOSE 63, which has a HLBvalue of about 9-10.

As noted above, such formulations are liquid at room temperature, notgels, hard fats, or any other solid form. The thickening agent serves toincrease viscosity, e.g., up to 10,000 cP (10,000 mPa-s), typically tono more than 5000 cP, and more typically to between 50 and 1000 cP. Insome such embodiments, the non-ionic surfactant, e.g., GELUCIRE orTEFOSE, may be solid at room temperature and require melting to effectmixing with the estradiol solubilized in fatty acid-glycol esters butthe resultant formulation is advantageously liquid, not solid.

The formulation of such embodiments is typically encapsulated in a softgelatin capsule or other soft capsule.

Typically, such formulations do not comprise a bioadhesive (i.e.,mucoadhesive) agent, a gelling agent, or a dispersing agent, or, atleast, do not comprise one or two of such components.

In more specific such formulations, the capsule shell, the activepharmaceutical ingredient, the fatty acid esters and the thickeningagent are the only essential ingredients. Non-essential ingredients,e.g., colorants, antioxidants or other preservatives, etc., may, ofcourse, be included but other ingredients in amounts that wouldmaterially change the solubility of the estradiol, the PK of theencapsulated formulation, the irritancy, vaginal discharge, intravaginalresidue, etc., e.g., other oils or fatty acid esters, lecithin,muco-adherent agents, gelling agents, dispersing agents, or the likewould not be included. Such embodiments of the invention may bedescribed as consisting essentially of the capsule shell, the activepharmaceutical ingredient, the fatty acid esters and the thickeningagent, as described in the immediately preceding paragraphs describingillustrative embodiments discovered to have favorable characteristics.

As an example of such embodiments discovered to have such favorablecharacteristics is mentioned the product identified in Example 3, below,as “Trial 5”.

EXAMPLES

In various embodiments, a vehicle system is created by dissolving anactive pharmaceutical ingredient (e.g., estradiol) in one or morepharmaceutically acceptable solubilizing agents. A vehicle system maythen be combined with a gel mass to create a final formulation suitablefor use in, for example, a vaginal suppository. In that regard, invarious embodiments, one or more vehicle systems may be combined withone or more gel masses. Other excipients may also be included in thevehicle system in various embodiments.

Example 1

Formulation: Vehicle System

In various embodiments, estradiol active pharmaceutical ingredient isprocured and combined with one or more pharmaceutically acceptablesolubilizing agents. Estradiol may be in micronized form ornon-micronized form. In various embodiments, the final formulationcomprises estradiol in a dosage strength of from about 1 mcg to about 25mcg.

Estradiol is combined with various pharmaceutically acceptablesolubilizing agents in various embodiments. As described above, CAPMULMCM, MIGLYOL 812, GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13, andTEFOSE 63(\may, alone or in various combinations, be used as apharmaceutically acceptable solubilizing agent in connection withestradiol.

Solubility of estradiol may affect final formulation stability anduniformity, so care should be taken when selecting an appropriatevehicle system. It is noted that surfactants are typically amphiphilicmolecules that contain both hydrophilic and lipophilic groups. Ahydrophilic-lipophilic balance (“HLB”) number is used as a measure ofthe ratio of these groups. It is a value between 0 and 20 which definesthe affinity of a surfactant for water or oil. HLB numbers arecalculated for nonionic surfactants, and these surfactants have numbersranging from 0-20. HLB numbers>10 have an affinity for water(hydrophilic) and number<10 have an affinity of oil (lipophilic).

In that regard, GELUCIRE 39/01 and GELUCIRE 43/01 each have an HLB valueof 1. GELUCIRE 50/13 has an HLB value of 13. TEFOSE 63 has an HLB valueof between 9 and 10.

Various combinations of pharmaceutically acceptable solubilizing agentswere combined with estradiol and examined. TABLE 1 contains the results.

TABLE 1 contains the following abbreviations: CAPMUL MCM (“MCM”),GELUCIRE 39/01 (“39/01”), GELUCIRE 43/01 (“43/01”), GELUCIRE50/13(“50/13”), and TEFOSE (“Tefose 63”).

TABLE 1 Physical state Physical @ state @ Room 37° C. after MeltingDispersion Vehicle Temper- ~30 Viscosity Time @ in water # system Ratioature minutes cps 37° C. 37° C.  1 MCM:39/01 8:2 Solid Clear liquid  50@ Start: 6 Small oil 37° C. min drops on Finish: 12 top min  2 MCM:39/017:3 Solid Clear liquid Start: 9 min Finish: 19 min  3 MCM:39/01 6:4Solid Clear liquid Start: 20 min Finish: 32 min  4 MCM:43/01 8:2 SolidLiquid with solid particles  5 MCM:43/01 7:3 Solid Liquid with solidparticles  6 MCM:50/13 9:1 Liquid/ Liquid/ 140 @ Clear Uniformly cloudycloudy 25° C. after 20 cloudy min dispersion  7 MCM:50/13 8:2 Liquid/Liquid/ 190 @ Uniformly cloudy cloudy 25° C. cloudy dispersion  8MCM:50/13 7:3 Semisolid Semisolid  9 MCM:TEFOSE 9:1 Semisolid Liquid/150 @ Start: 1 Uniformly 63 cloudy 25° C. min cloudy Finish: 5dispersion min 10 MCM:TEFOSE 8:2 Semisolid Semisolid 240 @ Uniformly 6325° C. cloudy dispersion 11 MCM:TEFOSE 7:3 Semisolid Semisolid 380 @Semisolid Uniformly 63 25° C. after 30 cloudy min at dispersion 37° C.,doesn't melt at 41° C. 12 MIGLYOL 9:1 Semisolid Semisolid 140 @ 2phases, 812: 50/13 25° C. oil on top 13 MIGLYOL 9:1 Liquid/ Liquid/ 90 @Start: 1 2 phases, 812: cloudy cloudy 25° C. min oil on top TEFOSE 63Finish: 5 min

Vehicle systems in TABLE 1 that were liquid or semisolid at roomtemperature were tested using a Brookfield viscometer (BrookfieldEngineering Laboratories, Middleboro, Mass.) at room temperature.Vehicle systems appearing in TABLE 1 that were solid at ambienttemperature were tested using a Brookfield viscometer at 37° C.

Vehicle systems appearing in TABLE 1 that were solid were placed at 37°C. to assess their melting characteristics. The results are in TABLE 1.It is noted that vehicle system 11 in TABLE 1 did not melt at 37° C. or41° C.

A dispersion assessment of the vehicle systems appearing in TABLE 1 wasperformed. The dispersion assessment was performed by transferring 300mg of each vehicle system in 100 ml of 37° C. water, without agitation,and observing for mixing characteristics.

Example 2

Formulation: Gel Mass

In various embodiments, a vehicle system may be combined with a gelmass. A gel mass may comprise, for example, gelatin (e.g., Gelatin, NF(150 Bloom, Type B)), hydrolyzed collagen (e.g., GELITA®, GELITA AG,Eberbach, Germany), glycerin, SORBITOL SPECIAL® (a sorbitan-sorbitolbased soft gel plasticizer), and/or other suitable materials in varyingproportions. SORBITOL SPECIAL® may be obtained commercially and may tendto act as a plasticizer and humectant.

Gel masses A through F were prepared according to the formulations inTABLE 2. Gel masses A through F differ in the proportion of one or morecomponents, for example.

TABLE 2 Gel A Gel B Gel C Gel D Gel E Gel F Ingredient % w/w % w/w % w/w% w/w % w/w % w/w Gelatin, NF (150 Bloom, Type B) 41.0 41.0 41.0 41.043.0 43.0 Glycerin 99.7%, USP 6.0 6.0 6.0 6.0 18.0 18.0 SorbitolSpecial, USP 15.0 15.0 15.0 15.0 GELITA ( hydrolyzed collagen) 3 3.0Citric acid 0.1 0.5 1 0.1 Purified Water 35.0 37.9 37.5 37.0 36.0 38.9Total 100.0 100.0 100.0 100.0 100.0 100.0 Dissolution gel strips, Avg of3 48 min 50 min 75 min 70 min (500 ml DH2O, 50 rpm @ (42, 45, 58) (50,51, 50) (76, 75, 74) (70, 71,70) 37° C.) Dissolution gel strips, Avg of3 72 min 82 min (500 ml pH 4 buffer, 50 rpm @ 70 min 84 min 37° C.)

Each gel mass A through F was prepared at a temperature range from about45° C. to about 85° C. Each molten gelatin mass A through F was castinto a film, dried and cut into strips. The strips were cut into uniformpieces weighing about 0.5 g, with about 0.5 mm thickness. Strips wereplaced into a USP Type 2 dissolution vessel in either water or pH 4buffer solution and the time for them to completely dissolve wasrecorded and listed in TABLE 2. It is noted that gel mass A has thefastest dissolution in both water and pH 4 buffer solution.

Example 3

Formulation: Final Formulation and Encapsulation

Various combinations of vehicle systems from TABLE 1 and gel masses fromTABLE 2 were prepared. The combinations are shown in TABLE 3.

TABLE 3 Trial Vehicle system Ratio Batch Size g Gel 1 MCM:39/01 8:2 750A 2 MCM:50/13 8:2 750 A 3 MCM:TEFOSE 63 8:2 750 A 4 MCM:TEFOSE 63 8:2750 B 5 MIGLYOL 812:TEFOSE 63 9:1 750 A

Estradiol was combined with each vehicle system so that about 10 mcg ofestradiol was contained within 300 mg of each vehicle system. Batch sizewas as listed in TABLE 3. To encapsulate the vehicle system, each 300 mgof vehicle system was combined with about 200 mg of the listed gel mass.Thus, for example, in Trial 1, MCM:39/01 in an 8:2 ratio was combinedwith gel A and 10 mcg of estradiol. In each final dosage, Trial 1comprised 300 mg of vehicle system, 200 mg of gel mass and 10 mcg ofestradiol. It should be noted, however, that in various embodiments thetotal mass of vehicle system, gel mass, and estradiol may be from about100 mg to about 1000 mg.

Each combination of vehicle system, estradiol, and gel mass may besuitable for use in, for example, a vaginal suppository.

Example 4

Estradiol Solubility

In various experiments, suitable solvents were determined for providingsufficient solubility to make 2 mg of estradiol in a 100 mg fill mass,with a desired goal of achieving ˜20 mg/g solubility for estradiol.Initial solubility experiments were done by mixing estradiol withvarious solvents, saturate the solution with the estradiol, equilibratefor at least 3 days and filter the un-dissolved particles and analyzingthe clear supernatant for the amount of estradiol dissolved by HPLC.

Estradiol solubility experiments were performed. From this list at leastone item (e.g. propylene glycol) is known to be unsuitable forencapsulation.

TABLE 4 Ingredient Solubility (mg/g) PEG 400 105*  Propylene Glycol 75*Polysorbate 80 36* TRANSCUTOL HP 141  CAPMUL PG8  31.2 *Literaturereference -Salole, E.G. (1987) The Physicochemical Properties ofOestradiol, J Pharm and Biomed Analysis, 5, 635-640.

In further solubility studies, estradiol was soluble at least 6 mg/gmMIGLYOL TRANSCUTOL in ratios of 81:19 to 95:5, in MIGLYOL; ethanol at91:11, and in MIGLYOLCAPMUL PG8 at 88:11, but not in MIGLYOLTRANSCUTOLat 96:4, MIGLYOLLabrasol at 70:30 to 80:20, or MIGLYOLCAPMUL PG8 at86:14.

Example 5

Process

With reference to FIG. 1, a method of making a fill material 100 isshown. Step 102 comprises heating a solubilizing agent to 40° C.±5° C.Heating may be accomplished through any suitable means. The heating maybe performed in any suitable vessel, such as a stainless steel vessel.The solubilizing agent may be any such solubilizing agent describedherein, for example, CAPMUL MCM.

Step 104 comprises mixing GELUCIRE with the solubilizing agent. As usedherein, any form of GELUCIRE may be used in step 104. For example, oneor more of GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13. may be usedin step 104. Mixing may be facilitated by an impeller, agitator, orother suitable means. Step 104 may be performed under an inert orrelatively inert gas atmosphere, such as nitrogen gas. Mixing may beperformed in any suitable vessel, such as a stainless steel vessel.

Step 106 comprises mixing estradiol into the mixture of the solubilizingagent and GELUCIRE. The estradiol may be mixed in micronized ornonmicronized form. Mixing may occur in a steel tank or other acceptablecontainer. Mixing may be facilitated by an impeller, agitator, or othersuitable means. Step 106 may be performed under an inert or relativelyinert gas atmosphere, such as nitrogen gas. In various embodiments,however, the addition of estradiol may be performed prior to step 104.In that regard, in various embodiments, step 106 is performed prior tostep 104.

Step 110 comprises preparing the gel mass. Any of the gel massesdescribed herein may be used in step 110. In that regard, gelatin (e.g.,Gelatin, NF (150 Bloom, Type B)), hydrolyzed collagen, glyercin, and/orother suitable materials may be combined at a temperature range fromabout 45° C. to about 85° C. and prepared as a film. Mixing may occur ina steel tank or other acceptable container. Mixing may be facilitated byan impellor, agitator, or other suitable means. Step 110 may beperformed under an inert or relatively inert gas atmosphere, such asnitrogen gas. Step 112 comprises degasing. The resulting mixture fromstep 112 may comprise a fill material suitable for production into asoftgel capsule.

In step 112, a soft gel capsule is prepared by combining the materialobtained in step 106 with the gel mass of step 110. The gel film may bewrapped around the material, partially or fully encapsulating it. Thegel film may also be injected or otherwise filled with the materialobtained in step 106.

Step 112 may be performed in a suitable die to provide a desired shape.Vaginal soft gel capsules may be prepared in a variety of geometries.For example, vaginal soft gel capsules may be shaped as a tear drop, acone with frustoconical end, a cylinder, a cylinder with larger “cap”portion, or other shapes suitable for insertion into the vagina. Vaginalsoft gel capsules in accordance with various embodiments may or may notbe used in connection with an applicator.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present disclosurewithout departing from the spirit or scope of the disclosure. Thus, itis intended that the present disclosure cover the modifications andvariations of this disclosure provided they come within the scope of theappended claims and their equivalents.

Likewise, numerous characteristics and advantages have been set forth inthe preceding description, including various alternatives together withdetails of the structure and function of the devices and/or methods.This disclosure is intended as illustrative only and as such is notintended to be exhaustive. It will be evident to those skilled in theart that various modifications may be made, especially in matters ofstructure, materials, elements, components, shape, size and arrangementof parts including combinations within the principles of the disclosure,to the full extent indicated by the broad general meaning of the termsin which the appended claims are expressed. To the extent that thesevarious modifications do not depart from the spirit and scope of theappended claims, they are intended to be encompassed therein.

What is claimed is:
 1. A soft gelatin vaginal insert containing a fillmaterial having a viscosity between 50 and 380 cP as measured at 25° C.,the fill material comprising one or more C6 to C14 fatty acid mono-,di-, or triesters of glycerol, a nonionic surfactant comprising PEG-6stearate and ethylene glycol palmitostearate, and 1 to 10 mcg ofestradiol, wherein estradiol is the only active ingredient in thevaginal insert; further wherein the insert is made by a processcomprising: a) making a pre-fill material consisting of: i. one or moreC6 to C14 fatty acid mono-, di-, or triesters of glycerol; ii. anonionic surfactant consisting of PEG-6 stearate, PEG-32 stearate, andethylene glycol palmitostearate; and iii. 1 to 10 mcg of estradiol; b)forming a soft gelatin capsule, c) filling the soft gelatin capsule withthe pre-fill material to make the insert.
 2. The soft gelatin vaginalinsert of claim 1, wherein the one or more C6 to C14 fatty acid mono-,di-, or triesters of glycerol is a C8 to C10 fatty acid triglyceridecomposition that is at least about 80% by weight caprylic (C8) acid andcapric (C10) acids.
 3. The soft gelatin vaginal insert of claim 1,wherein forming the pre-fill material comprises: a) optionally heatingone or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol;b) adding the nonionic surfactant to the one or more C6 to C14 fattyacid mono-, di-, or triesters of glycerol to form a mixture; and c)adding estradiol to the mixture.
 4. The soft gelatin vaginal insert ofclaim 3, wherein heating is not optional.
 5. The soft gelatin vaginalinsert of claim 4, wherein heating comprises heating the one or more C6to C14 fatty acid mono-, di-, or triesters of glycerol to a temperatureranging from about 35° C. to about 45° C.
 6. The soft gelatin vaginalinsert of claim 1, wherein the fill material contained within the softgelatin capsule has a mass of about 300 mg.
 7. The soft gelatin vaginalinsert of claim 1, wherein the pre-fill material comprises a 9:1 ratioof one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerolto nonionic surfactant.
 8. The soft gelatin vaginal insert of claim 1,wherein the nonionic surfactant has an HLB value of less than about 10.9. The soft gelatin vaginal insert of claim 1, wherein the nonionicsurfactant has an HLB value of about 9 to about
 10. 10. The soft gelatinvaginal insert of claim 1, wherein the insert is shaped with a widerbottom portion and a narrower top portion.
 11. The soft gelatin vaginalinsert of claim 1, wherein the vaginal insert is in the shape of a teardrop.
 12. A soft gelatin vaginal insert consisting essentially of a softgelatin capsule containing a fill material, the fill material consistingessentially of 1 to 10 mcg of estradiol and a solvent system, thesolvent system consisting essentially of a 9:1 ratio of one or more C6to C14 fatty acid mono-, di-, or triesters of glycerol to a nonionicsurfactant consisting essentially of PEG-6 stearate, PEG-32 stearate,and ethylene glycol palmitostearate, wherein the fill material has aviscosity of between 50 and 380 cP as measured at 25° C.
 13. The softgelatin vaginal insert of claim 12, wherein the soft gelatin capsuleconsists essentially of 150 bloom, Type B gelatin, hydrolyzed collagen,glycerin, and, optionally, a sorbitan-sorbitol based soft gelplasticizer.
 14. The soft gelatin vaginal insert of claim 12, whereinthe fill material has a mass of about 300 mg.
 15. The soft gelatinvaginal insert of claim 12, wherein the capsule has an interior wallsurface defining an inner space, wherein a maximal length defined by twopoints on opposing sides of the interior wall surface is about 0.69inches.
 16. The soft gelatin vaginal insert of claim 12, wherein thecapsule has an interior wall surface defining an inner space and anexterior wall surface disposed over the interior wall surface defining athickness, wherein the thickness measured perpendicular to the interiorwall surface and the exterior wall surface is about 0.108 inches.
 17. Asoft gelatin vaginal insert comprising a soft gelatin capsule containinga fill material, the fill material comprising 1 to 10 mcg of estradioland a solvent system, the solvent system consisting essentially of a 9:1ratio of (i) one or more C6 to C14 fatty acid mono-, di-, or triestersof glycerol to (ii) an excipient composition that does not increase theirritancy of the solvent system, the fill material having a viscosity ofbetween 50 and 380 as measured at 25° C.
 18. The soft gelatin vaginalinsert of claim 17, wherein the excipient composition has an HLB valueof less than about
 10. 19. The soft gelatin vaginal insert of claim 17,wherein the excipient composition has an HLB value of about 9 to about10.
 20. The soft gelatin vaginal insert of claim 17, wherein the insertis shaped with a wider bottom portion and a narrower top portion. 21.The soft gelatin vaginal insert of claim 17, wherein the vaginal insertis in the shape of a tear drop, a cone with a frustoconical end, or acylinder with a wider cap portion.